Keywords
Labrune syndrome - leukoencephalopathy - cerebral calcifications - cysts
Introduction
Leukoencephalopathy, cerebral calcifications, and cysts (LCC) form a very rare association
which is termed “Labrune syndrome” after Labrune who reported the first case in 1996.[1] Clinical features include repeated seizures, gradual reduction of cognition, pyramidal,
and extrapyramidal symptoms. CT features are extensive calcifications involving bilateral
basal ganglia and bilateral deep cerebellar nuclei. MRI demonstrates extensive abnormal
white matter hyperintensity suggesting leukoencephalopathy. Development of large parenchymal
cysts causes complications like compression and pressure effect on surrounding structures
necessitating surgical treatment.[1]
[2] Histopathology shows mainly angiomatous changes and cystic gliotic areas.[1] We report a case of LCC and discuss the findings with review of literature.
Case Report
A 26-year-old male patient with complaints of generalized tonic-clonic seizures, giddiness
with imbalance, and slowly progressive motor symptoms for 7 years was referred to
us for MRI brain. General physical, ophthalmologic, and neurological examinations
did not reveal any significant abnormality. Initially the neurological examination
revealed reduced muscle power (four-fifth) on the right side with mild spasticity
which was progressive. Complete blood count, liver and renal function tests, sedimentation
rate, calcium, phosphate, alkaline phosphatase, lactate levels, serum thyroid, and
parathyroid hormones revealed no abnormality. Cytomegalovirus, toxoplasma gondii,
hydatid cyst, HIV 1, and 2 serological tests were all negative. No significant abnormality
was seen on cervical, thoracic, and abdominal CT examinations.
MRI of brain revealed multiple varying sized round to oval cystic lesions appearing
uniformly hyperintense to CSF on T2, variably hyperintense to CSF on FLAIR, and uniformly
hypointense on T1 scattered throughout the white matter of bilateral cerebral hemispheres
([Figs. 1],[2],[3]). These lesions did not show restriction of diffusion and showed peripheral post-contrast
enhancement. The cyst in the high parietal region showed a small area of blood–fluid
level. These lesions caused a mass effect in the form of compression of the frontal
horn and body of right lateral ventricle, third ventricle and bilateral cerebral peduncles
and mild midline shift to left. There was extensive T2 and FLAIR hyperintensity in
the subcortical and deep white matter of bilateral cerebral hemispheres. There were
extensive calcifications involving bilateral caudate nuclei, putamina, thalami, right
cerebral peduncle ([Fig. 4]).
Fig. 1 (A and B) T2 W MRI axial images show the multiple cystic lesions (thin black arrows), diffuse white matter hyperintense signal in white matter (thick black arrows) of bilateral cerebral hemispheres.
Fig. 2 (A and B) FLAIR MRI axial images show the multiple cystic lesions (thin black arrows), diffuse white matter hyperintense signal in white matter (thick black arrows) of bilateral cerebral hemispheres.
Fig. 3 (A and B) T1 W MRI axial images show the multiple cystic lesions (thin black arrows) in the bilateral cerebral hemispheres.
Fig. 4 (A and B) T2 FFE GRE axial images show the multiple calcifications (white arrows) in the bilateral caudate, putamina, thalami, right cerebral peduncle, and bilateral
cerebral white matter.
The patient had undergone multiple serial MRI brain examinations and a single CT brain
from the onset of the clinical symptoms at the age of 19 years. On comparing with
those previous studies there was a significant increase in the number, size, and distribution
of the cerebral cystic lesions with increase in the mass effect on surrounding structures.
Also, there was an increase in the extensive T2 and FLAIR hyperintensity in the subcortical
and deep white matter of bilateral cerebral hemispheres which was suggestive of leukoencephalopathy.
The calcifications also increased in size and distribution.
Discussion
The combination of cerebral cysts, calcifications, perilesional white matter edema
generally directs to the consideration of a parasitic infection, especially, cysticercosis
or echinococcus alveolaris infection. Nonetheless no serologic or histopathologic
confirmatory evidence was found. Thus, considering the rare association of cerebral
cysts, basal ganglia calcifications, and supratentorial cysts, we began with literature
search. Our case resembled exactly with LCC previously described by Labrune et al[1] and Nagae-Poetscher[2] et al. The main imaging features of LCC were extensive brain calcifications, leukodystrophy,
and formation of parenchymal cysts.[1] The main symptoms and signs are cognitive decline, convulsive seizure, pyramidal,
extrapyramidal, and/or cerebellar signs. The patients present with the clinical features
generally from early infancy to adolescence. Our patient presented with his first
generalized seizure at 19 years of age. Initially his seizures were rare and responded
well to anticonvulsant drug therapy. The pyramidal symptoms developed 4 to 5 years
after the first convulsive seizure. Six years later, he had slowly progressive motor
symptoms in the form of right-sided weakness and slurring of speech. This slow evolution
of the disease in our patient is in line with the very slow progression rate described
for LCC.
The clinical course of LCC is mild, however, a serious and continuous degeneration
of the nervous system was shown on neuroimaging. Increased white matter signal intensity
relatively sparing the U fibers and corpus callosum, cerebral cysts, extensive coarse
calcifications in the basal ganglia, brain stem, and subcortical white matter in our
case were similar to those of other cases described in the literature. During the
course of the 7 years many of the cysts enlarged gradually and caused mass effect
and compression of the close structures such as ventricles and cerebral peduncles.
The increase in the size of the cysts may be the effect of continuous increase in
fluid content of the white matter.[1]
[2] Similar circumstance was also seen in other conditions, such as leukoencephalopathies
and some intracranial tumors.[3]
[4]
[5] Coalition of the microcysts containing edema fluid could be a probable mechanism
for the increase in size of cysts. The expansion of cysts in our case may be the result
of such a mechanism.
The main differentials considered were hydatid, cysticercosis, and cryptococcosis.
Neurocysticercosis would present with multiple cystic lesions with variable parenchymal
calcifications.[6] HIV patients with cryptococcosis present with parenchymal calcifications and gelatinous
pseudocysts.[7] Nonetheless no serologic or histopathologic confirmatory evidence was found. Also,
leukoencephalopathy has not been described with these entities. Fahr's disease presents
with extensive basal ganglia and cerebellar nuclei calcifications. Nonetheless the
other findings of LCC are not the features of Fahr's disease. Children who receive
chemotherapy and radiotherapy for malignancies also show features of basal ganglia
calcifications with white matter changes. Coat's disease in association with leukoencephalopathy,
cysts, and calcification has been called as “Coat's plus.”[8] Unilateral retinal telangiectasia with exudation commonly occurring in boys sporadically
without systemic features is referred to as Coat's disease. Bilateral retinal telangiectasia
with exudation along with systemic features in the form of LCC is referred to as “Coat's
plus.” The ophthalmologic examination in our case was normal, thus ruling out the
possibility of “Coat's plus.” Cerebroretinal microangiopathy with calcification and
cysts (CRMCC) incorporates both LCC and Coat's plus diseases.[9]
There is a controversy surrounding the etiopathogenesis of LCC. The basic abnormality
found in histopathological examination was obliterative microangiopathy.[1] It is hypothesized that the necrotic process secondary to obliterative microangiopathy
is the cause for cyst formation and calcification is the result of dystrophic calcification.
White matter abnormal hyperintense signal is due to changes in water content and not
due to myelination abnormality.
Gross pathology specimens revealed external cerebral and cerebellar parenchymal moderate
edema. Leptomeninges were thin and shiny with focally congested vessels. Serial cut
sections revealed multiple variable sized cysts predominantly in white matter and
few in subcortical area with few foci of calcification. These cysts were filled with
mucoid gelatinous material ([Fig. 5]).
Fig. 5 Gross autopsy specimen reveals variable sized cysts (black arrow) predominantly in white matter and few in subcortical area with few foci of calcification
(white arrows) with focally congested vessels in the leptomeninges.
Edematous changes in the brain parenchyma, exaggerated proliferation of abnormal small
vessels, significant gliosis, and micro calcifications were the chief histopathological
findings reported by Labrune et al in two of three patients of Labrune syndrome. The
chief histopathological findings in our specimen were angiomatous changes in the form
of abnormal prominent congested vessels, multiple cystic areas with gelatinous eosinophilic
contents resembling plasma, foci of dystrophic calcification in the cerebral parenchyma
and vessel wall, many foci of gliosis, Rosenthal fibers and histiocytic aggregates
with cholesterol clefts. These findings are consistent with LCC ([Figs. 6],[7],[8]).
Fig. 6 (A and B) Reveals multiple variable sized cysts with gelatinous eosinophilic contents.
Fig. 7 (A and B) Reveals dystrophic calcification in the cerebral parenchyma and vessel wall.
Fig. 8 (A and B) Reveals foci of gliosis, Rosenthal fibers, and histiocytic aggregates with cholesterol
clefts.
In conclusion, although there is definitive imaging association in the form of the
triad in LCC, the exact etiology of the triad remains unknown. Nonetheless LCC represents
a specific recognizable clinic-radiologic entity. The most noticeable histopathologic
feature is cerebral angiomatous changes. In spite of these relatively characteristic
imaging and histopathologic findings, the clinical features are not uniform.
Thus, it may be contemplated that the older onset age, normal intelligence, and very
slow progression, as in our patient, may indicate the presence of the adult form of
this rare disease.
